Hematology. American Society of Hematology. Education Program最新文献

Adoptive T-cell therapy has emerged as a transformative modality in cancer immunotherapy, building upon foundational principles established in allogeneic hematopoietic stem cell transplantation. In this setting, while donor T cells mediate curative graft-versus-leukemia and graft-versus-infection effects, their alloreactivity poses significant risks. Gene transfer strategies-such as suicide gene insertion-have enabled the safer use of donor lymphocytes by allowing the selective elimination of T cells in case of adverse events. With this initial gene therapy approach, several lessons on the function, persistence, safety, and efficacy of engineered T cells were learned. More recently, advances in genome editing technologies have enabled precise manipulation of T-cell genomes and function, including disruption of endogenous T-cell receptors (TCRs) and insertion of tumor-specific receptors, such as chimeric antigen receptors and tumor-specific TCRs. Integration of T-cell manufacturing protocols optimized for persistence and resistance to immune suppression-largely facilitated by the possibility to simultaneously edit multiple genes (multiplex genome editing) in the same cells-has positioned engineered T cells as programmable and persistent therapeutics. Here, we briefly review key milestones, challenges, and innovations in T-cell gene engineering, from allogeneic hematopoietic stem cell transplantation to next-generation TCR-edited immunotherapies.

Immunotherapies have significantly transformed the treatment landscape of acute leukemia in adults, most notably in B-cell acute lymphoblastic leukemia (B-ALL). Blinatumomab and inotuzumab ozogamicin have become established treatments, enhancing remission rates, measurable residual disease clearance, and overall survival in relapsed/refractory disease, and these agents, are now increasingly incorporated into frontline therapy. Additionally, autologous CD19 chimeric antigen receptor (CAR) T-cell therapy has dramatically improved salvage treatment outcomes, demonstrating exceptional remission rates and durable responses even in heavily pretreated patients. Enhanced understanding of mechanisms underlying disease resistance and relapse is guiding the development of optimized combination and sequential therapeutic approaches. In acute myeloid leukemia (AML), gemtuzumab ozogamicin has shown significant clinical benefits, particularly in molecularly defined subsets. Ongoing research focuses on novel antibody-drug conjugates, immune cell engagers, and advanced cellular therapies, facing challenges primarily in selecting appropriate targets and overcoming the immunosuppressive tumor microenvironment. For T-cell acute lymphoblastic leukemia (T-ALL), therapeutic innovation is confronted with unique challenges due to overlapping antigen expression between malignant, normal, and CAR T-cells. Promising early clinical and preclinical studies are currently evaluating anti-CD38 antibodies and CAR T-cells mostly directed against CD5 and CD7. This review highlights how immunotherapy has reshaped treatment paradigms across acute leukemias, underscoring successful experiences in B-ALL. These insights emphasize the need for continued innovation to overcome existing hurdles in AML and T-ALL, ultimately aiming to enhance patient outcomes and quality of life.

Cytopenias are common in the adult population, with increasing recognition of clonal hematopoiesis and inherited syndromes due to widespread molecular testing. Clonal hematopoiesis is a premalignant spectrum of disorders characterized by a somatic myeloid mutation, including clonal hematopoiesis of indeterminate potential and clonal cytopenia of uncertain significance. Inherited bone marrow failure syndromes (IBMFS) can also be found during workup of incidental cytopenias, even in the absence of other syndromic associations. In clonal cytopenia of uncertain significance, the overall risk of progressing to a myeloid neoplasm can be affected by the type of mutation, number of mutations, and variant allele frequency. Prognostication systems, such as the Clonal Hematopoiesis Risk Score, MN-predict, and Clonal Cytopenia Risk Score, can help determine the risk of malignant progression. Context-dependent factors like chemotherapy, radiation, and smoking can influence this risk. For suspected IBFMS, workup typically includes telomere length testing and chromosomal breakage analysis, along with comprehensive germline testing. If IBMFS is confirmed, further testing may be indicated based on the syndrome, as patients are often at risk of other organ dysfunction and malignancies. In these patients, stem cell transplantation may be indicated.

Atypical hemolytic uremic syndrome (aHUS) is a rare, life-threatening thrombotic microangiopathy characterized by uncontrolled activation of the complement pathway, leading to microangiopathic hemolytic anemia, thrombocytopenia, and organ damage. The advent of complement inhibitors such as eculizumab and ravulizumab has transformed aHUS management, markedly reducing morbidity and mortality. However, long-term therapy presents challenges, including infection risks, economic burden, and the need for indefinite treatment. Discontinuing complement inhibition is a pivotal clinical decision that requires careful risk assessment to prevent relapse. Pathogenic gene variants in complement- regulating proteins, particularly CFH, CFI, MCP/CD46, and C3, significantly increase the risk of relapse, particularly within the first 3 to 12 months after cessation. Patients with multiple pathogenic variants or variants of uncertain significance exhibit heightened vulnerability, necessitating extended monitoring. Clinical predictors such as young age, prior kidney transplantation, and the presence of extrarenal manifestations further stratify relapse risk. Additionally, dynamic biomarkers such as elevated soluble C5b-9 at the time of discontinuation may signal imminent relapse. Comprehensive postdiscontinuation surveillance, including laboratory assessment of kidney function, hemolysis markers, and complement activity, is crucial for early relapse detection. Emerging strategies for personalized risk assessment, including pharmacogenomic profiling and biomarker-guided monitoring, may optimize therapeutic decision-making in aHUS. This review synthesizes current evidence on the long-term management of aHUS, focusing on strategies for anticomplement therapy discontinuation, relapse prediction, and individualized monitoring.

Improved understanding of the molecular underpinnings of acute leukemia has led to advances in the detection of very low levels of leukemia-specific abnormalities, known as measurable residual disease (MRD). The limit of detection for modern next-generation sequencing and polymerase chain reaction-based assays is as low as 10-6, allowing for quantitative and longitudinal monitoring in both acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). In the period surrounding allogeneic hematopoietic cell transplantation (HCT), detectable MRD is clearly associated with poor outcomes, primarily due to an increased risk of morphologic relapse. In this review, we address the use of maintenance therapy for patients with acute leukemia, including those who are MRD-positive prior to and following HCT. Post-HCT azacitidine may have a role for MRD-positive AML. In AML with FLT3-internal tandem duplication mutation, post-HCT gilteritinib and sorafenib can be evidence-based strategies to target MRD. In ALL, blinatumomab is a powerful tool to eradicate MRD in patients with Philadelphia (Ph)-positive or Ph-negative ALL; tyrosine kinase inhibitors are indicated for post-HCT management of Ph+ ALL. Despite these advances, the optimal duration and type of intervention still remain unknown for many patients with acute leukemia who have peri-HCT MRD.

Pregnant persons with bleeding disorders (pwBD) have an increased risk of primary and secondary postpartum hemorrhage (PPH). Patients with von Willebrand disease, a bleeding disorder of unknown cause, or qualitative platelet defects (QPDs) and hemophilia carriers (HC) may or may not naturally achieve an adequately hemostatic state due to the hypercoagulable changes of pregnancy. PwBD greatly benefit from receiving care in a multidisciplinary setting including hematologists, obstetricians, anesthesiologists, and clinical geneticists. Factor levels should be obtained, at minimum, prior to conception as baseline as well as at the 34- to 36-week mark for delivery planning. However, target factor levels for delivery remain controversial given that many bleeding phenotypes do not predictably correlate with levels. Hemostatic therapies include antifibrinolytic agents, desmopressin, factor concentrates, and blood components such as cryoprecipitate, plasma, and platelets. Antifibrinolytics such as tranexamic acid have the most robust evidence for PPH management, though factor concentrates are now routinely utilized in certain circumstances. Blood products are an option for pwBD who have QPDs or when factor concentrates are not available. In patients with certain bleeding disorders, such as HCs, mode-of-delivery discussions must include consideration of the risks both to the affected neonate and to the mother. We favor selecting the mode of delivery based upon maternal indications whenever possible. Post partum, therapies may be continued for days or sometimes weeks after delivery, as pwBD are at high risk for delayed PPH.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired disorder of complement dysregulation, predisposing patients to complications of intravascular hemolysis, thrombophilia, and marrow failure, with a high risk of mortality without treatment. Allogeneic stem cell transplantation is the only current cure but is typically reserved for marrow failure-predominant disease or when targeted therapies are not available. Terminal complement inhibition with eculizumab has significantly altered management and outcomes for patients with PNH, and the last several years have seen the development and approval of many new complement inhibitors with different molecular targets. Newer inhibitors may also provide options for extended time between doses, for self-administration, and for management of iatrogenic extravascular hemolysis, which can occur secondary to C5 inhibition. This essay reviews the various therapeutic options potentially available to PNH patients, the pros and cons of each treatment, considerations regarding the monitoring of side effects, and the possible complications, as well as breakthrough hemolysis and an approach to shared decision-making.

The treatment landscape for hemophilia has evolved rapidly over the past decade, with the approval of several therapies with novel mechanisms of action. Extended half-life factor concentrates and nonfactor therapies, including factor VIII mimetics and rebalancing agents, have reduced treatment burden while also improving bleed protection. Although these new therapies provide an unprecedented ability to personalize treatment and to meet changing needs across the life span for each individual, the complexity of these treatment considerations has made clinical decision-making and selection of the optimal treatment challenging for those living with hemophilia and their clinicians.

Precursor states such as clonal hematopoiesis of indeterminate potential (CHIP) and clonal cytopenia of undetermined significance, carry distinct risks for progression to myeloid neoplasms and age-related comorbidities. While biologically distinct, idiopathic cytopenia of undetermined significance is also a differential diagnostic consideration for these precursor lesions. Through 3 illustrative cases, we highlight the diagnostic complexity and clinical relevance of these entities, emphasizing the need for integrated clinical, morphologic, and molecular assessment to guide individualized patient care. Emerging evidence suggests that CHIP contributes not only to hematopoietic stem cell aberrations and potential myeloid neoplasia but also to cardiovascular disease and solid-tumor outcomes, reinforcing its significance as a systemic biomarker. We summarize the current risk stratification tools and ongoing clinical trials aimed at modulating inflammation and clonal dynamics in CH-associated conditions. We also outline our approach from our Clonal Hematopoiesis Clinic, which incorporates surveillance, preventive care, and clinical trial enrollment. Establishing standardized diagnostic criteria, harmonizing trial frameworks, and formally incorporating CHIP into hematology, oncology, cardiology, and survivorship paradigms will be essential to reducing long-term morbidity and improving patient outcomes.

Red cell transfusions represent the main treatment of acute blood loss anemia; however, there are patients who are unable or refuse to receive blood products. Further, in all patients, it is essential to only transfuse when the benefits of transfusion outweigh the risks. In those patients who are unable to receive a blood transfusion, it is important to have a multidisciplinary treatment plan. Further, for those patients requiring surgery, it is important to consider the pre-, intra-, and postoperative periods. Many of the principles and strategies outlined in this article can be applied to patients across clinical contexts and are not exclusive to the surgical setting. Before any planned surgery or intervention, all patients should be screened for anemia at least 6 weeks prior to their anticipated surgical or delivery date. Anemia should be corrected, and the patient's bleeding history should be documented. Strategies to reduce blood loss intraoperatively should be discussed with the surgical and anesthetic team. A plan for emergency management of bleeding and treatment to reduce risk, both intraoperatively and postoperatively, should be developed. The patient's decisions about which, if any, blood products or fractions are acceptable should be documented. Intraoperatively, surgical and anesthetic techniques to minimize bleeding should be used along with appropriate medications. Postoperatively, considerations include the minimization of blood sampling, ongoing support of the patient's hemoglobin mass, and optimization of the physiologic tolerance of anemia. Options exist to allow for the safe and effective management of patients who refuse or are unable to receive blood transfusions. It is essential to have clear communication and documentation of the goals of therapy as well as acceptable interventions. The involvement of a multidisciplinary team to manage the patient is essential.